The general goal of our investigations is to define the basis of immunodeficiency that occurs during aging in mice in relation to genetics. The central control of the involution of the immunologic network is the thymus and its functions. During the previous year we have studied in vitro in several strains of mice (young and old) T and B cell functions with particular reference to determine the functions that decline earlier during aging. The involution of the thymus and its system has been correlated with longevity and the occurrence of autoimmunity and malignancy. We have found three different ways to prolong lifespan in mice: 1) By calorie restriction, 2) cellular manipulation and 3) hybrid combinations between short- and long-lived strains of mice. Attempts will be continued to further define the immunologic basis of longer survival in mice fed less calories and given thymus grafts and stem cells. Additionally, we propose to begin to analyze the relationship between histocompatibility genes, longevity and tumor-susceptibility. Genetic experiments will be performed to extend the observations of the advantage of heterozygosis at H-2 loci in survival. F1 and F2 hybrids and backcrosses using long- and short-lived mice will be useful for analysis of cellular deficits, autoantibodies, tumor development, survival and H-2 genotypes. These experiments will attempt to show that thymic involution may influence pathogenesis of diseases of aging whereas etiology requires a genetically programmed system involving genes linked to the major transplantation loci. Understanding of these relationships should ultimately help prolong useful life in man. BIBLIOGRAPHIC REFERENCES: Good, R.A., Fernandes, G., Yunis, E.J., et al: Nutritional deficiency, immunologic function and disease. Am. J. Path. 84:599-614, 1976. Yunis, E.J., Fernandes, G., Smith, J. and Good, R.A.: Long survival and immunologic reconstitution following transplantation with syngeneic or allogeneic fetal liver and neonatal spleen cell. Trans. Proc. 8:521-525, 1976.